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. 2012 May-Jun;88(3):596-603.
doi: 10.1111/j.1751-1097.2011.01039.x. Epub 2011 Dec 20.

Miconazole induces fungistasis and increases killing of Candida albicans subjected to photodynamic therapy

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Miconazole induces fungistasis and increases killing of Candida albicans subjected to photodynamic therapy

Sara B Snell et al. Photochem Photobiol. 2012 May-Jun.

Abstract

Cutaneous and mucocutaneous Candida infections are considered to be important targets for antimicrobial photodynamic therapy (PDT). Clinical application of antimicrobial PDT will require strategies that enhance microbial killing while minimizing damage to host tissue. Increasing the sensitivity of infectious agents to PDT will help achieve this goal. Our previous studies demonstrated that raising the level of oxidative stress in Candida by interfering with fungal respiration increased the efficiency of PDT. Therefore, we sought to identify compounds in clinical use that would augment the oxidative stress caused by PDT by contributing to reactive oxygen species (ROS) formation themselves. Based on the ability of the antifungal miconazole to induce ROS in Candida, we tested several azole antifungals for their ability to augment PDT in vitro. Although miconazole and ketoconazole both stimulated ROS production in Candida albicans, only miconazole enhanced the killing of C. albicans and induced prolonged fungistasis in organisms that survived PDT using the porphyrin TMP-1363 and the phenothiazine methylene blue as photosensitizers. The data suggest that miconazole could be used to increase the efficacy of PDT against C. albicans, and its mechanism of action is likely to be multifactorial.

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Figures

Figure 1
Figure 1. Structures of azole antifungal agents used in this study
Imidazole antifungal agents include miconazole, clotrimazole and ketoconazole. Fluconazole is a triazole.
Figure 2
Figure 2. Miconazole enhances the fungicidal activity PDT of against C. albicans in vitro
Effects of PDT alone (TMP-PDT) were compared to those observed when C. albicans SC5314 was exposed to miconazole alone (Mcz) and when irradiation was performed following a 2 h incubation with 25 μg/ml miconazole at 37° C (Mcz+TMP-PDT). Organism killing was determined by a colony forming unit (CFU) assay. Results are expressed as a log10 reduction in CFU compared to untreated cells as a control. Data represent the mean ± S.D. of three experiments performed in duplicate.
Figure 3
Figure 3. Growth inhibition of C. albicans by combined miconazole+TMP-PDT but not by combined fluconazole+TMP-PDT
TMP-PDT was performed on organisms left untreated, treated with either miconazole (Mcz, 25 μg/ml = 52.2 μM) or fluconazole (Flc, 25 μg/ml = 81.6 μM) for 2 h prior to irradiation. Cells were serially diluted 10-fold in dH2O; 2 μl of each dilution was spotted on YPD plates and incubated at 37°C. The top six rows show cells incubated 24 h; the bottom row shows cells treated with miconazole + PDT after 48 h incubation.
Figure 4
Figure 4. Increased time of exposure to miconazole enhances the fungicidal action of PDT using TMP-1363
Organisms were either left untreated (−) or pre-treated with miconazole (Mcz) for 2 h prior to PDT. Samples in the top four rows were irradiated, but not treated with TMP-1363 (−); samples in the lower four rows were irradiated in the presence of TMP-1363 (+). Post-PDT, cells were serially diluted 10-fold in either water (−) or in 25 μg/ml Mcz prior to spotting 2 μl on YPD, followed by 48 h incubation at 37°C.
Figure 5
Figure 5. Effects of combined imidazole+TMP-PDT on production of reactive oxygen species (ROS) by C. albicans
Organisms were treated in a 6-well tissue culture dish with the corresponding imidazole (Mcz -miconazole; Clt -clotrimazole; Ktz -ketoconazole) at 25 μg/ml and H2DCFDA (5 μg/ml) for 2 h prior to PDT. Induction of fluorescence of H2DCFDA (19, 20)after oxidation was used as an indicator of ROS production. Following PDT, fluorescence was measured (Ex = 485 nm/Em = 538 nm). Data are expressed as relative fluorescence units, and represent the mean ± S.D. of two experiments performed in duplicate.
Figure 6
Figure 6. Imidazole induction of ROS in C. albicans does not correlate with either growth inhibition or increased sensitivity to PDT using TMP-1363
Cells from the different experimental groups were serially diluted 10-fold in dH2O, and 2 μl of each dilution was spotted in duplicate on YPD plates. Images of irradiated samples were taken following 24 and 48 h of incubation at 37°C.
Figure 7
Figure 7. Miconazole exposure following methylene blue-PDT enhances growth inhibition and killing of C. albicans
Counter-clockwise from the bottom, right: methanol vehicle alone, 2.5 μg, 12.5 μg or 62.5 μg miconazole was added to the disc. Images of plates were taken following 24 and 48 h of incubation at 37°C.

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